Gene Therapy for SCID
Overview Severe combined immunodeficieny disease, otherwise known as SCID or the "bubble boy" disease is characterized by a lack of a functioning immune system. The primary feature of this disease is lack or defect in the B and T cells which esstentially make up the adaptive immune response and are responsible for fighting off infections and protecting the body from foreign pathogens. Therefore patients are extemely susceptible to serious illnesses such as pneumonia, chicken pox, meningitis and bloodstream infections (1). Since they have no system to fight them off, these infections are normally recurrent and can cause death in patients commonly before the age of one or early childhood. It is therefore crucial without treatment, that the person with the condition remain in a "germ free" environment in order to avoid common bacterial and viral pathogens. Types of SCID X-linked SCID: This recessive version of SCID is passed down via the X chromosome and accounts for nearly 50% of all SCID cases (2). This version of SCID results in a mutation in the interleukin 2 receptor gamma gene which is an essential part of multiple IL receptors. Defects in this receptor lead to disruptions in the signalling pathway that results in the formation of normal lymphocyte cells (2). ADA-SCID: This form of SCID is the result of a defect of a gene on chromosome 20 that causes a lack of the enzyme adenosine deaminase. Without this enyzme present the substrate accumulates to levels in the body that are extremely toxic to developing lymphoid cells and therefore they do not mature (2). Treatment Methods As of today, the majority of SCID cases are treated by the invasive procedure hematopoietic stem cell transplants (bone marrow transplants). This essentially replaces the patient's lack of immune system with a healthy functioning one capable of producing normal immune cells and reponses. However this requires a closely matched donor HSC in order for the transplant to be around 80% successful. If the donor is not in fact closely matched, graft vs. host disease, morbidity, and death can result (3). In the case of ADA based SCID enyzme replacement therapy can be used to increase the amount of functional deaminase present. However this is also not 100% effective and thus the immune response is not fully restored (3). Therefore increased risk of infection is still extremely common in these patients. Gene Therapy Methods Since there are obvious complications associated with the above treatment methods, gene therapy clinical trials have been conducted in humans with varying degrees of success. In past and current clinical trials patients hematopoietic stem cells are taken from the patient and then transduced via a viral vector with the corrected genes to create HSC and progentior cells transduced with the gene of interest. This cells are then infused back into the patients(3). In the first patient clinical trials, multiple patients developed T cell acute lymphoblastic leukemia. This was believed to be caused by the delivery method, gammaretroviral vector. Since this virus has its own intact promoter sequence and enhancer elements when the virus inserted into the patients genome within or near the LMO-2 gene (a proto-oncogene) this caused uncontrolled upregulation and thus cancer development in these patients(3). In more recent clinical trials, the viral vector does not contain a promoter sequence and the transduced gene of interest is transcribed in the host by an internal promoter with the hope of not affecting other nearby gene regulation(3). Two studies following this method are described below: ADA SCID Clinical Trial results: 6 children with ADA SCID were treated with the autologous C D34+ HSC and progenitor cells transduced with the corrected gammaretroviral vector containing a functional ADA gene (4). After 43 months it was noted that 4 of the 6 patients had improved immune function. In the other 2 patients treatment failed due to current infections and other technical reasons and therefore were placed back on ERT treatment plans. In the 4 successful patients is was noted that the subtrate toxicity levels lowered as a result of a functional ADA enzyme), and no recurrent infections or leukemia were reported (4). SCID-IX (X-linked) Clincal Trial results: 10 children with X-linked SCID were treated again with the autologous CD34 + HSC and progenitor cells transduced with the corrected gammaretroviral vector containing a functional interleukin 2 receptor gamma gene (5). After 80 months a function polyclonal T cell system was reported in all patients but only some of the patients had enough recovered humoral immunity (B cell production) to allow them to stop using immunoglobin supplements. 3 of the patients who did stop using the supplements developed severe respiratory infections, but they were responsive to antibiotics. It was also noted that 1 patient did develop T cell acute lymphoblastic leukemia from insertional mutagenesis caused by the viral vector upregulating the LMO-2 gene. This patient entered remission through chemotherapy though, and still maintained a functional polyclonal T cell system (5). As a final note it was mentioned that this therapy proved effect in high survival rates for up to 9 years in the patients. Resources 1. Ballard, Barb. "The SCID Homepage." The SCID Homepage. Severe Combined Immunodeficiency, 2014. Web. 15 Oct. 2014. 2."Severe Combined Immunodeficiency." Genes and Diseases. Besthesda: NCBI, 1998. 3. Beals, Jacquelyn K. "Gene Therapy for Severe Combined Immunodeficiency." Medscape Medical News. Medscape, 26 Aug. 2011. 4.Gaspar, Bobby H. "Hematopoietic Stem Cell Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Leads to Long-Term Immunological Recovery and Metabolic Correction." Science Translational Medicine 3.97 (August 2011): 80-97. AAAS. Web. 5. Gaspar, Bobby H. "Long-Term Persistence of a Polyclonal T Cell Repertoire After Gene Therapy for X-Linked Severe Combined Immunodeficiency." Science Translational Medicine 3.97 (August 2011): 79-97. AAAS.